Can Storage Stability and Simulated Gastrointestinal Behavior Change the Cytotoxic Effects of Concentrated Guava Leaves Extract against Human Lung Cancer Cells?

The influence of storage stability and simulated gastrointestinal behavior of different extracts of guava leaves extracts (NC: not concentrated, and C10 and C20: concentrated by nanofiltration) was evaluated based on their total phenolic compound (TPC) contents and antioxidant activity as well as on their cytotoxic effects on A549 and Vero cells. The results showed that C10 and C20 presented high stability for 125 days probably due to their high TPC contents and antioxidant activity. The simulated gastrointestinal behavior modified their TPC contents; however, after all digestion steps, the TPC values were higher than 70%, which means that they were still available to exert their bioactivities. Additionally, the cytotoxic effects of these extracts were evaluated before and after the simulated gastrointestinal behavior or under different storage conditions. C10 presented the best selectivity indices (SI) values (IC50 Vero cells/IC50 A549 cells) at both conditions suggesting that it can be considered a potential extract to be developed as a functional food due to its resistance to the gastrointestinal digestion and storage conditions tested.

Prevention of drug diversion and substance use disorders among anesthesiologists: a narrative review

Abstract Diversion of substances from the care of the intended patient is a significant problem in healthcare. Patients are harmed by the undertreatment of pain and suffering, transmission of disease, as well as the risk associated with impaired vigilance. Healthcare providers may be harmed by the physical and mental impact of their addictions. Healthcare systems are placed in jeopardy by the legal impact associated with illegal routes of drug release including sanction and financial liability and loss of public trust. Healthcare institutions have implemented many measures to reduce diversion from the perioperative area. These efforts include education, medical record surveillance, automated medication dispensing systems, urine drug testing, substance waste management systems, and drug diversion prevention teams. This narrative review evaluates strengths, weaknesses, and effectiveness of these systems and provides recommendations for leaders and care providers.

Prevention of drug diversion and substance use disorders among anesthesiologists: a narrative review.

Diversion of substances from the care of the intended patient is a significant problem in healthcare. Patients are harmed by the undertreatment of pain and suffering, transmission of disease, as well as the risk associated with impaired vigilance. Healthcare providers may be harmed by the physical and mental impact of their addictions. Healthcare systems are placed in jeopardy by the legal impact associated with illegal routes of drug release including sanction and financial liability and loss of public trust. Healthcare institutions have implemented many measures to reduce diversion from the perioperative area. These efforts include education, medical record surveillance, automated medication dispensing systems, urine drug testing, substance waste management systems, and drug diversion prevention teams. This narrative review evaluates strengths, weaknesses, and effectiveness of these systems and provides recommendations for leaders and care providers.

One year follow-up on a randomized study investigating serratus anterior muscle and pectoral nerves type I block to reduced neuropathic pain descriptors after mastectomy.

Breast cancer is the second most common diagnosed type of cancer in women. Chronic neuropathic pain after mastectomy occurs frequently and is a serious health problem. In our previous single-center, prospective, randomized controlled clinical study, we demonstrated that the combination of serratus anterior plane block (SAM) and pectoral nerve block type I (PECS I) with general anesthesia reduced acute postoperative pain. The present report describes a prospective follow-up study of this published study to investigate the development of chronic neuropathic pain 12 months after mastectomy by comparing the use of general anesthesia alone and general anesthesia with SAM + PECS I. Additionally, the use of analgesic medication, quality of life, depressive symptoms, and possible correlations between plasma levels of interleukin (IL)-1 beta, IL-6, and IL-10 collected before and 24 h after surgery as predictors of pain and depression were evaluated. The results showed that the use of SAM + PECS I with general anesthesia reduced numbness, hypoesthesia to touch, the incidence of patients with chronic pain in other body regions and depressive symptoms, however, did not significantly reduce the incidence of chronic neuropathic pain after mastectomy. Additionally, there was no difference in the consumption of analgesic medication and quality of life. Furthermore, no correlation was observed between IL-1 beta, IL-6, and IL-10 levels and pain and depression. The combination of general anesthesia with SAM + PECS I reduced the occurrence of specific neuropathic pain descriptors and depressive symptoms. These results could promote the use of SAM + PECS I blocks for the prevention of specific neuropathic pain symptoms after mastectomy.Registration of clinical trial: The Research Ethics Board of the Hospital Sirio-Libanes/Brazil approved the study (CAAE 48721715.0.0000.5461). This study is registered at Registro Brasileiro de Ensaios Clinicos (ReBEC), and ClinicalTrials.gov, Identifier: NCT02647385.

Effects of Lipophilicity and Structural Features on the Antiherpes Activity of Digitalis Cardenolides and Derivatives.

There is growing interest in exploring Digitalis cardenolides as potential antiviral agents. Hence, we herein investigated the influence of structural features and lipophilicity on the antiherpes activity of 65 natural and semisynthetic cardenolides assayed in vitro against HSV-1. The presence of an α,ß-unsaturated lactone ring at C-17, a ß-hydroxy group at C-14 and C-3ß-OR substituents were considered essential requirements for this biological activity. Glycosides were more active than their genins, especially monoglycosides containing a rhamnose residue. The activity enhanced in derivatives bearing an aldehyde group at C-19 instead of a methyl group, whereas inserting a C-5ß-OH improved the antiherpes effect significantly. The cardenolides lipophilicity was accessed by measuring experimentally their log P values (n-octanol-water partition coefficient) and disclosed a range of lipophilicity (log P 0.75±0.25) associated with the optimal antiherpes activity. In silico studies were carried out and resulted in the establishment of two predictive models potentially useful to identify and/or optimize novel antiherpes cardenolides. The effectiveness of the models was confirmed by retrospective analysis of the studied compounds. This is the first SAR study addressing the antiherpes activity of cardenolides. The developed computational models were able to predict the active cardenolides and their log P values.

Development of a cell-based reporter assay for detection of Human alphaherpesviruses.

Immunosuppressed patients can suffer from Human alphaherpesvirus (HSV) infection with fast evolution, severe atypical symptomatology, and often-fatal outcome. Thus, the development and validation of new methods in vitro and in vivo to promote an early diagnosis and effective treatment of these patients are crucial. Therefore, this work aimed to develop a cell-based reporter assay for the detection of HSV through the transfection of Vero cells with the ICP10 promoter from HSV-2 linked to the pZsGreen1-1 plasmid. The assay was evaluated on Vero cells infected with HSV-1 or HSV-2 and followed by treating them with anti-HSV agents (acyclovir, gallic acid, convallatoxin, and Uncaria sp. extract) or with no anti-HSV activity agents (Passiflora edulis extract and cardenolide derivatives). The GFP expression was increased by both HSV cellular infection, which was detected by flow cytometry and fluorescence microscopy. F2R Zsgreen1-1 cells infection with 200 and 600 PFU/mL of HSV-2 increased the fluorescence intensity, when compared to the controls, by approximately 30% and 60%, respectively. Infection with 100 and 600 PFU/mL of HSV-1 also increased the fluorescence intensity by approximately 20% and 35%, when compared to the controls, respectively. The F2R ZsGreen1-1 system revealed to be an efficient assay, which can be used for clinical diagnosis, antiviral resistance evaluation, HSV cycle studies, and new antiviral drug research.

A New Saquinavir Mesylate-Sodium Decyl Sulfate Salt Discovered by Serendipity during an Anomalous Dissolution Test.

PURPOSE: To understand the anomalous behavior of Saquinavir Mesylate (SQVM) in sodium decyl sulfate (SDS) medium during a dissolution test through a crystallographic analysis of the crystal obtained. As a result, it will be possible to elucidate its crystal structure and carry out a complete solid-state characterization of the API. METHODS: The solid form obtained was characterized by a structural analysis through X-ray single crystal and powder diffraction. The crystallographic structures of the new salt and the SQVM were compared. In addition, a complete solid-state characterization of SQVM raw material was carried out by techniques such as diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), Raman spectroscopy, scanning electron microscopy and a dissolution method. RESULTS: A new salt consisting of SQVM and SDS was crystallized and its crystal structure was elucidated and reported herein for the first time. The anionic part of SDS interacts with the cationic segment of SQVM to obtain a new salt designated as SQV-DS, which precipitates. The main difference between the two structures occurs in the c-axis expansion, which increases from 15.966 (5) to 21.1924 (14), respectively. CONCLUSIONS: Some of the strategies to enhance the dissolution rate of poorly aqueous soluble APIs include the use of surfactants such as SDS in the dissolution medium, as well as in the formulated products. However, there have been constant reports of a dissolution rate slowdown by some surfactants. The interaction mechanisms between the APIs and the dissolution medium containing surfactants need to be carefully investigated in current pharmaceutical formulations. Graphical Abstract.

Noninvasive intracranial pressure real-time waveform analysis monitor during prostatectomy robotic surgery and Trendelenburg position: case report.

Both robotic surgery and head-down tilt increase intracranial pressure by impairing venous blood outflow. Prostatectomy is commonly performed in elderly patients, who are more likely to develop postoperative cognitive disorders. Therefore, increased intracranial pressure could play an essential role in cognitive decline after surgery. We describe a case of a 69-year-old male who underwent a robotic prostatectomy. Noninvasive Brain4careTM intraoperative monitoring showed normal intracranial compliance during anesthesia induction, but it rapidly decreased after head-down tilt despite normal vital signs, low lung pressure, and adequate anesthesia depth. We conclude that there is a need for intraoperative intracranial compliance monitoring since there are major changes in cerebral compliance during surgery, which could potentially allow early identification and treatment of impaired cerebral complacency.

Drug abuse amongst anesthetists in Brazil: a national survey.

BACKGROUND: The prevalence of Substance Use Disorders (SUD) and acceptance of drug testing among anesthetists in Brazil has not been determined. METHODS: An internet-based survey was performed to investigate the prevalence of SUD among anesthetists in Brazil, to explore the attitudes of anesthetists regarding whether SUD jeopardizes the health of an impaired provider or their patient, and to determine the provider's perspective regarding acceptance and effectiveness of drug testing to reduce SUD. The questionnaire was distributed via social media. REDCap was utilized to capture data. A sample size of 350 to achieve a confidence level of 95% and confidence interval of 5 was estimated. Study report was based on STROBE and CHERRIES statements. RESULTS: The survey was returned from 1,295 individuals. Most individuals knew an anesthesia provider with a SUD (82.07%), while 23% admitted personal use. The most common identified substances of abuse were opioids (67.05%). Very few respondents worked in a setting that performs drug testing (n = 17, 1.33%). Most individuals believed that drug testing could improve personal safety (82.83%) or the safety of patients (85.41%). Individuals with a personal history of SUD were less likely to believe in the effectiveness of drug testing to reduce one's own risk (74.92% vs. 85.18%, p < 0.0001) or improve the safety of patients (76.27% vs. 88.13%, p < 0.001). CONCLUSIONS: SUDs are common among anesthetists in Brazil. Drug testing would be accepted as a viable means to reduce the incidence although a larger study should be performed to investigate the logistical feasibility.

Matrix Effects of the Hydroethanolic Extract of Calyces of Physalis peruviana L. on Rutin Pharmacokinetics in Wistar Rats Using Population Modeling.

Rutin is the rutinose conjugate of quercetin. It presents several biological activities and is the major flavonoid in the hydroalcoholic extract of the calyces of Physalis peruviana L. It also shows hypoglycemic activity after oral administration. The aim of this work was to study the matrix effects of the extract from P. peruviana calyces on the pharmacokinetics of rutin and its metabolites in Wistar rats, using non-compartmental and population pharmacokinetic analyses. A pharmacokinetic study was performed after intravenous and oral administration of different doses of pure rutin and the extract. In the non-compartmental analysis, it was found that rutin from the extract exhibited higher distribution and clearance, as well as an 11-fold increase in the bioavailability of its active metabolites. A population pharmacokinetic model was also carried out with two compartments, double absorption and linear elimination, in which the extract and the doses were the covariates involved. This model correctly described the differences observed between rutin as a pure compound and rutin from the extract, including the dose dependency.

The Protective Action of Rubus sp. Fruit Extract Against Oxidative Damage in Mice Exposed to Lipopolysaccharide.

Neuroinflammation is an event that occurs in several pathologies of brain. Rubus sp. (blackberry) is a powerful antioxidant fruit, and its extract has neuroprotective activity. The aim of this study was to investigate the blackberry extract properties on lipopolysaccharide (LPS)-induced neuroinflammation, in relation to oxidative parameters and acetylcholinesterase activity in the brain structures of mice. We also investigated interleukin-10 levels in serum. Mice were submitted to Rubus sp. extract treatment once daily for 14 days. On the fifteenth day, LPS was injected in a single dose. LPS induced oxidative brain damage and the blackberry extract demonstrated preventive effects in LPS-challenged mice. LPS administration increased reactive oxygen species levels in the cerebral cortex and striatum, as well as lipid peroxidation in the cerebral cortex. However, the blackberry extract prevented all these parameters. Furthermore, LPS decreased thiol content in the striatum and hippocampus, while a neuroprotective effect of blackberry extract treatment was observed in relation to this parameter. The blackberry extract also prevented a decrease in catalase activity in all the brain structures and of superoxide dismutase in the striatum. An increase in acetylcholinesterase activity was detected in the cerebral cortex in the LPS group, but this activity was decreased in the Rubus sp. extract group. Serum IL-10 levels were reduced by LPS, and the extract was not able to prevent this change. Finally, we observed an antioxidant effect of blackberry extract in LPS-challenged mice suggesting that this anthocyanin-rich extract could be considered as a potential nutritional therapeutic agent for preventive damage associated with neuroinflammation.

Cytotoxicity of glucoevatromonoside alone and in combination with chemotherapy drugs and their effects on Na+,K+-ATPase and ion channels on lung cancer cells.

Cardiac glycosides (CGs) are useful drugs to treat cardiac illnesses and have potent cytotoxic and anticancer effects in cultured cells and animal models. Their receptor is the Na+,K+ ATPase, but other plasma membrane proteins might bind CGs as well. Herein, we evaluated the short- and long-lasting cytotoxic effects of the natural cardenolide glucoevatromonoside (GEV) on non-small-cell lung cancer H460 cells. We also tested GEV effects on Na+,K+ -ATPase activity and membrane currents, alone or in combination with selected chemotherapy drugs. GEV reduced viability, migration, and invasion of H460 cells spheroids. It also induced cell cycle arrest and death and reduced the clonogenic survival and cumulative population doubling. GEV inhibited Na+,K+-ATPase activity on A549 and H460 cells and purified pig kidney cells membrane. However, it showed no activity on the human red blood cell plasma membrane. Additionally, GEV triggered a Cl-mediated conductance on H460 cells without affecting the transient voltage-gated sodium current. The administration of GEV in combination with the chemotherapeutic drugs paclitaxel (PAC), cisplatin (CIS), irinotecan (IRI), and etoposide (ETO) showed synergistic antiproliferative effects, especially when combined with GEV + CIS and GEV + PAC. Taken together, our results demonstrate that GEV is a potential drug for cancer therapy because it reduces lung cancer H460 cell viability, migration, and invasion. Our results also reveal a link between the Na+,K+-ATPase and Cl- ion channels.

Phytogenic blend protective effects against microbes but affects health and production in broilers.

The aim of this study was to determine whether addition of a phytogenic blend in the feed of broilers to replace conventional antimicrobials as a performance enhancer would improve or maintain productive efficiency. The phytogenic blend was based on curcuminoids, cinnamaldehyde and glycerol monolaurate. We used 480 birds divided into three groups with eight repetitions per group and 20 birds per repetition. The groups were identified as antimicrobial-treated: basal feed with antibiotics and coccidiostatic agents; phytogenic blend: basal feed with blend; and control, only basal feed. Zootechnical performance was measured on days from 1 to 42, with body weight measured at days 1, 7, 21 and 42. We collected excreta for parasitological analysis and total bacterial counts to determine if the phytogenic blend had kept the bacteria and coccidia in counts smaller or similar to that resulting from use of conventional performance enhancer. Other variables were also measured to complement our research, i.e., if the consumption of bend is good for the health of the birds (without causing toxicity and negatively altering the metabolism and intestinal morphometry) and does not interfere in the quality of the meat. Because the bacteria are often opportunistic, we challenged all birds at 23 days of age with high doses of oral oocysts (28,000 oocysts). Birds supplemented with the blend showed inferior performance compared to birds in the control and antimicrobial treated group (P < 0.05). We found a smaller number of oocysts of Eimeria spp. in the excreta at 42 days in the treatment with blend and antimicrobial treated group (P < 0.05). In terms of total bacterial counts, there were lower counts in the birds of the blend group than in the control group (P < 0.05). The blend increased the yellow intensity and the luminosity of the meat (P < 0.05), as well as cooking weight losses (P < 0.05) compared those of the control. We observed higher total levels of saturated fatty acids in meat from the blend and antimicrobial treated group (P < 0.05), as well as lower levels of monounsaturated fatty acids in the blend group (P < 0.05). The inclusion of a phytogenic blend to replace conventional antimicrobials and anticoccidial agents in the diet of chickens was able to control bacteria as well as coccidia; however, it ends up harming health and production.